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ABT-199,BCL-2inhibitor

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产品名称: ABT-199,BCL-2inhibitor
产品型号: M60075-2s
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简单介绍

ABT-199,BCL-2inhibitor


ABT-199,BCL-2inhibitor  的详细介绍
Product Information
Chemical Name: (4-(4-{[2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl]methyl}piperazin-1-yl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide)
Molecular Weight: 868.44
Formula: C45H50ClN7O7S
Purity: ≥ 98%
CAS#: 1257044-40-8
Solubility: DMSO up to 50 mM
Storage: Powder: 4oC 1 year DMSO: 4oC 3 month -20oC 1 year


Biological Activity:

ABT-199 is a highly potent, selective, and orally bioavailable BCL-2 inhibitor. ABT-199 has picomolar affinity for BCL-2 (Ki < 0.010 nM) and > 1000 folds selectivity over BCL-XL (Ki = 48 nM) and BCL-W (Ki = 245 nM). Therefore, ABT-199 is a much improved lead compound over the original ABT-263 (navitoclax) to avoid thrombocytopenia caused by BCL-XL inhibition. ABT-199’s cell-killing effect is selective and mechanism dependent. It can potently kill BCL-2-overexpressing FL5.12 cells (EC50 ~ 4 nM) and RS4;11 BCL-2–dependent ALL cells (EC50 ~8 nM), but showed much weaker activity against BCL-XL-overexpressing FL5.12 cells (EC50 ~261 nM) and H146 ALL cells (EC50 ~4,260 nM). ABT-199 inhibits the growth of BCL-2–dependent human hematological tumors in vivo and spares human platelets as a single agent or in combination with rituximab and bendamustine. A single dose of ABT-199 in three patients with refractory chronic lymphocytic leukemia resulted in tumor lysis within 24 h. These data indicates that selective pharmacological inhibition of BCL-2 shows promise for the treatment of BCL-2–dependent hematological cancers.


How to Use:

In vitro:  ABT-199 was used at 0.1-1 µM final concentration in vitro and in cellular assays.

In vivo: ABT-199 was orally dosed to mice at 12.5-100 mg/kg once per day in combination with rituximab and Bendamustine, and significantly reduced tumor volume.


Reference:

    1. 1. Fresquet V, et al. Acquired mutations in BCL2 family proteins conferring resistance to the BH3 mimetic ABT-199 in lymphoma. (2014) Blood. 123(26):4111-9. 
    2. 2. Souers AJ, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. (2013) Nat Med. 19(2):202-8.
    3. 3. Roberts, A.W. et al. Selective inhibition of BCL-2 is active against chronic lymphocytic leukemia (CLL): first clinical experience with the BH3-mimetic ABT-199. Abstract 546 (European Hematology Association 2012, Amsterdam, The Netherlands, June 14–17, 2012).


             

             


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